The hallmark of polycystic ovary syndrome (PCOS) is high
circulating androgen concentrations or hyperandrogenemia.
Hyperandrogenemia coupled with a high fat, western style diet puts
PCOS patients at risk for obesity and metabolic syndrome. In
addition to abberrant steroidogenic enzyme function in PCOS
patients, hyperinsulinemia may drive excessive production of
androgens by the adrenal, ovary, and possibly the adipose tissue.
Evidence suggests that insulin resistance is higher in women whose
white adipose tissue distribution is predominantly visceral.
Interestingly, the role of androgens in glucose homeostasis is
sexually dimorphic, with insulin resistance occurring in hyperandrogenemic
females but in hypoandrogenemic males.
In fact, sex specific effects of androgens and their interaction
with other sex steroids could explain differential body fat
deposition and insulin sensitivity between females and males.

Preliminary data generated in our laboratory in lean pigs
indicates that testosterone may cause hyperinsulinemia systemically
in addition to resulting in abnormal insulin signaling in adipose
tissue, particularly the visceral adipose tissue compartment.
Subsequent in vitro experiments performed in our laboraotry with
induced, cultured rat adipocytes have demonstrated that female rat
adipocytes collected during proestrus (i.e. high estradiol) are
more sensitive than male rat adipocytes to the effects of androgens
on the insulin signaling cascade at the gene transcript level.
Adipocytes derived from the visceral adipose tissue compartment in
female rats respond to the potent androgen, dihydrotestosterone,
with down regulation of insuling signaling cascade components at
the gene transcript level and decreased abundance of
phosphorylated, activated proteins in the insulin signaling
cascade. By contrast, adipocytes derived from the visceral
adipose tissue compartment in male rats show no significant
response in insulin signaling cascade proteins to androgen
treatment.

The short-term goal of this portion of our
research program is to establish proof of concept that androgens
down-regulate distinct insulin-signaling pathway components in
visceral versus subcutaneous adipose tissue of females and that
this response is differentially affected by estradiol and
progesterone and the development of obesity.